Streptokinase and urokinase have been widely applied to the treatment of thrombosis and obstructive diseases including cerebral thrombosis, peripheral arterial obstruction, peripheral venous obstruction and acute myocardial infarction.
However, it has been pointed out that the application of these drugs would be accompanied by some side effects such as a decrease in circulating fibrinogen or hemorrhage. Therefore, there have been attempts to develop a thrombolytic drug which is more safe and more effective than conventional ones and yet exerts a specific effect on fibrin.
The signle-chain structure of single-chain prourokinase, which is one of the thrombolytic drugs having specific attraction to fibrin, can be incised by treating the same with plasmin. Thus, urokinase of double-chain type, which is the conventionally known urokinase (hereinafter referred to as double-chain urokinase) is obtained.
A plasminogen activator (PA) such as urokinase activates plasminogen circulating in blood to convert it to plasmin which in turn can dissolve thrombi. It is the thrombolytic effect caused by the activation of plasminogen that plays an important role in thrombolysis.
Since double-chain urokinase is an activating type, it mainly activates plasminogen in blood and thereby causes lysis of thrombi. Accordingly, double chain urokinase can cause systemic fibrinolysis, for example, by the decomposition of fibrinogen by the produced, circulating plasmin. In contrast thereto, the plasminogen-activating effect of single-chain prourokinase is significantly lower than that of double-chain urokinase. Even if single-chain pro-urokinase should activate circulating plasminogen to form a trace amount of plasmin, the activity of the plasmin is inhibited by .alpha.2-PI which is a plasmin inhibitor exerting an immediate-type, intense antiplasmin activity. Thus, single-chain prourokinase hardly activates plasminogen. In addition, since single-chain pro-urokinase has a high affinity for fibrin, its thrombolytic effect is mainly caused by the activation of plasminogen in thrombi and systemic fibrinolysis is rarely induced.
On the other hand, it is possible to enhance the fibrinolytic activity of urokinase by increasing the amount of available plasminogen, which is the substrate of the plasminogen activator, i.e., urokinase, to thereby promote the formation of plasmin. It is well known that the combined use of double-chain urokinase and plasminogen would enhance the former's fibrinolytic activity (cf. V.V. Kakkar, M. F. Scully, Haemostasis, 18, suppl. 1, 127 (1988); and V. Tilsner, G. Witte, ibid., 139 (1988)).